From Fundamentals to Innovation in Alzheimer's Disease: Molecular Findings and Revolutionary Therapies

Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut-brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy.